Impact of a Cancer-Associated Mutation on Poly(ADP-ribose) Polymerase1 Inhibition

Abstract

Poly(ADP-ribose) polymerase1 (PARP1) plays a vital role in DNA repair and its inhibition in cancer cells may cause cell apoptosis. In this study, we investigated the effects of a PARP1 variant, V762A, which is strongly associated with several cancers in humans, on the inhibition of PARP1 by three FDA approved inhibitors: niraparib, rucaparib and talazoparib. Our work suggests that these inhibitors bind to the V762A mutant more effectively than to the wild-type (WT), with similar binding free energies between them. Talazoparib inhibition uniquely lowers the average residue fluctuations in the mutant than the WT including lower fluctuations of mutants N- and C-terminal residues, conserved H-Y-E traid residues and donor loop (D-loop) residues which important for catalysis more effectively than other inhibitions. However, talazoparib also enhances destabilizing interactions between the mutation site in the HD domain in the mutant than WT. Further, talazoparib inhibition significantly disrupts the functional fluctuations of terminal regions in the mutant, which are otherwise present in the WT. Lastly, the mutation and inhibition do not significantly affect PARP1s essential dynamics. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=144 SRC="FIGDIR/small/623412v1_fig1a.gif" ALT="Figure 1A"> View larger version (45K): org.highwire.dtl.DTLVardef@4d4562org.highwire.dtl.DTLVardef@10643dborg.highwire.dtl.DTLVardef@511ae2org.highwire.dtl.DTLVardef@bc2403_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure.C_FLOATNO Impact of V762A mutation on inhibition of PARP1. C_FIG